Devices and methods for non-invasive capacitive electrical stimulation and their use for vagus nerve stimulation on the neck of a patient

ABSTRACT

A non-invasive electrical stimulation device shapes an elongated electric field of effect that can be oriented parallel to a long nerve, such as a vagus nerve in a patient&#39;s neck, producing a desired physiological response in the patient. The stimulator comprises a source of electrical power, at least one electrode and a continuous electrically conducting medium in which the electrode(s) are in contact. The stimulation device is configured to produce a peak pulse voltage that is sufficient to produce a physiologically effective electric field in the vicinity of a target nerve, but not to substantially stimulate other nerves and muscles that lie between the vicinity of the target nerve and patient&#39;s skin. Current is passed through the electrodes in bursts of preferably five sinusoidal pulses, wherein each pulse within a burst has a duration of preferably 200 microseconds, and bursts repeat at preferably at 15-50 bursts per second.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/222,087 filed Aug. 31, 2011, which is a continuation-in-partof U.S. patent application Ser. No. 13/183,765 filed Jul. 15, 2011 whichclaims the benefit of priority of U.S. Provisional Patent ApplicationNo. 61/488,208 filed May 20, 2011 and is a continuation-in-part to U.S.patent application Ser. No. 13/183,721 filed Jul. 15, 2011, which claimsthe benefit of priority of U.S. Provisional Patent Application No.61/487,439 filed May 18, 2011 and is a continuation-in-part of U.S.patent application Ser. No. 13/109,250 filed May 17, 2011, which claimsthe benefit of priority of U.S. Provisional Patent Application No.61/471,405 filed Apr. 4, 2011 and is a continuation-in-part of U.S.patent application Ser. No. 13/075,746 filed Mar. 30, 2011, which claimsthe benefit of priority of U.S. provisional patent application61/451,259 filed Mar. 10, 2011 and is a continuation-in-part of U.S.patent application Ser. No. 13/005,005 filed Jan. 12, 2011, which is acontinuation-in-part of U.S. patent application Ser. No. 12/964,050filed Dec. 9, 2010, which claims the benefit of priority of U.S.Provisional Patent Application No. 61/415,469 filed Nov. 19, 2010 and isa continuation-in-part of U.S. patent application Ser. No. 12/859,568filed Aug. 9, 2010, which is a continuation-in-part of U.S. patentapplication Ser. No. 12/408,131 filed Mar. 20, 2009 and acontinuation-in-part application of U.S. patent application Ser. No.12/612,177 filed Nov. 9, 2009 the entire disclosures of which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Itrelates more specifically to the use of non-invasive devices andmethods, particularly transcutaneous electrical nerve stimulationdevices that make use of capacitive electrical coupling, as well asmethods of treating patients using energy that is delivered by suchdevices. The disclosed methods and devices may be used to stimulate thevagus nerve of a patient to treat many conditions, such as: headachesincluding migraine and cluster headaches, rhinitis and sinusitis,depression and anxiety disorder, post-operative ileus, dysfunctionassociated with TNF-alpha in Alzheimer's disease, postoperativecognitive dysfunction, postoperative delirium, rheumatoid arthritis,asthmatic bronchoconstriction, urinary incontinence and/or overactivebladder, and sphincter of Oddi dysfunction, as well as neurodegenerativediseases more generally, including Alzheimer's disease and its precursormild cognitive impairment (MCI), Parkinson's disease (includingParkinson's disease dementia) and multiple sclerosis.

Treatments for various infirmities sometime require the destruction ofotherwise healthy tissue in order to produce a beneficial effect.Malfunctioning tissue is identified and then lesioned or otherwisecompromised in order to produce a beneficial outcome, rather thanattempting to repair the tissue to its normal functionality. A varietyof techniques and mechanisms have been designed to produce focusedlesions directly in target nerve tissue, but collateral damage isinevitable.

Other treatments for malfunctioning tissue can be medicinal in nature,but in many cases the patients become dependent upon artificiallysynthesized chemicals. In many cases, these medicinal approaches haveside effects that are either unknown or quite significant.Unfortunately, the beneficial outcomes of surgery and medicines areoften realized at the cost of function of other tissues, or risks ofside effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue holds significant promise for the treatment ofmany ailments, because such stimulation is generally a wholly reversibleand non-destructive treatment.

Nerve stimulation is thought to be accomplished directly or indirectlyby depolarizing a nerve membrane, causing the discharge of an actionpotential; or by hyperpolarization of a nerve membrane, preventing thedischarge of an action potential. Such stimulation may occur afterelectrical energy, or also other forms of energy, are transmitted to thevicinity of a nerve [F. RATTAY. The basic mechanism for the electricalstimulation of the nervous system. Neuroscience 89 (2, 1999):335-346;Thomas HEIMBURG and Andrew D. Jackson. On soliton propagation inbiomembranes and nerves. PNAS 102 (28, 2005): 9790-9795]. Nervestimulation may be measured directly as an increase, decrease, ormodulation of the activity of nerve fibers, or it may be inferred fromthe physiological effects that follow the transmission of energy to thenerve fibers.

One of the most successful applications of modern understanding of theelectrophysiological relationship between muscle and nerves is thecardiac pacemaker. Although origins of the cardiac pacemaker extend backinto the 1800's, it was not until 1950 that the first practical, albeitexternal and bulky, pacemaker was developed. The first truly functional,wearable pacemaker appeared in 1957, and in 1960, the first fullyimplantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by stimulating thesacral nerve roots at the bottom of the spinal cord (see U.S. Pat. No.6,871,099 to WHITEHURST, et al., the disclosure of which is incorporatedherein by reference).

Electrical stimulation of the brain with implanted electrodes has alsobeen approved for use in the treatment of various conditions, includingmovement disorders such as essential tremor and Parkinson's disease. Theprinciple underlying these approaches involves disruption and modulationof hyperactive neuronal circuit transmission at specific sites in thebrain. Unlike potentially dangerous lesioning procedures in whichaberrant portions of the brain are physically destroyed, electricalstimulation is achieved by implanting electrodes at these sites. Theelectrodes are used first to sense aberrant electrical signals and thento send electrical pulses to locally disrupt pathological neuronaltransmission, driving it back into the normal range of activity. Theseelectrical stimulation procedures, while invasive, are generallyconducted with the patient conscious and a participant in the surgery.

However, brain stimulation, and deep brain stimulation in particular, isnot without some drawbacks. The procedure requires penetrating theskull, and inserting an electrode into brain matter using acatheter-shaped lead, or the like. While monitoring the patient'scondition (such as tremor activity, etc.), the position of the electrodeis adjusted to achieve significant therapeutic potential. Next,adjustments are made to the electrical stimulus signals, such asfrequency, periodicity, voltage, current, etc., again to achievetherapeutic results. The electrode is then permanently implanted, andwires are directed from the electrode to the site of a surgicallyimplanted pacemaker. The pacemaker provides the electrical stimulussignals to the electrode to maintain the therapeutic effect. While thetherapeutic results of deep brain stimulation are promising, significantcomplications may arise from the implantation procedure, includingstroke induced by damage to surrounding tissues and theneuro-vasculature.

Most of the above-mentioned applications of electrical stimulationinvolve the surgical implantation of electrodes within a patient. Incontrast, for embodiments of the present invention, the discloseddevices and medical procedures stimulate nerves by transmitting energyto nerves and tissue non-invasively. They may offer the patient analternative that does not involve surgery. A medical procedure isdefined as being non-invasive when no break in the skin (or othersurface of the body, such as a wound bed) is created through use of themethod, and when there is no contact with an internal body cavity beyonda body orifice (e.g, beyond the mouth or beyond the external auditorymeatus of the ear). Such non-invasive procedures are distinguished frominvasive procedures (including minimally invasive procedures) in thatinvasive procedures do involve inserting a substance or device into orthrough the skin or into an internal body cavity beyond a body orifice.For example, transcutaneous electrical nerve stimulation (TENS) isnon-invasive because it involves attaching electrodes to the surface ofthe skin (or using a form-fitting conductive garment) without breakingthe skin. In contrast, percutaneous electrical stimulation of a nerve isminimally invasive because it involves the introduction of an electrodeunder the skin, via needle-puncture of the skin (see commonly assignedco-pending US Patent Application 2010/0241188, entitled PercutaneousElectrical Treatment of Tissue to ERRICO et al, which is herebyincorporated by reference in its entirety).

Potential advantages of non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures generally present fewer problems withbiocompatibility. In cases involving the attachment of electrodes,non-invasive methods have less of a tendency for breakage of leads, andthe electrodes can be easily repositioned if necessary. Non-invasivemethods are sometimes painless or only minimally painful and may beperformed without the need for even local anesthesia. Less training maybe required for use of non-invasive procedures by medical professionals.In view of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace, and the cost of non-invasive procedures may be reducedrelative to comparable invasive procedures.

Electrodes that are applied non-invasively to the surface of the bodyhave a long history, including electrodes that were used to stimulateunderlying nerves [L. A. GEDDES. Historical Evolution of Circuit Modelsfor the Electrode-Electrolyte Interface. Annals of BiomedicalEngineering 25 (1997):1-14]. However, electrical stimulation of nervesin general fell into disfavor in middle of the twentieth century, untilthe “gate theory of pain” was introduced by Melzack and Wall in 1965.This theory, along with advances in electronics, reawakened interest inthe use of implanted electrodes to stimulate nerves, initially tocontrol pain. Screening procedures were then developed to determinesuitable candidates for electrode implantation, which involved firstdetermining whether the patient responded when stimulated withelectrodes applied to the surface of the body in the vicinity of thepossible implant. It was subsequently found that the surface stimulationoften controlled pain so well that there was no need to implant astimulating electrode [Charles Burton and Donald D. Maurer. PainSuppression by Transcutaneous Electronic Stimulation. IEEE Transactionson Biomedical Engineering BME-21(2, 1974): 81-88]. Such non-invasivetranscutaneous electrical nerve stimulation (TENS) was then developedfor treating different types of pain, including pain in a joint or lowerback, cancer pain, post-operative pain, post-traumatic pain, and painassociated with labor and delivery [Steven E. ABRAM. TranscutaneousElectrical Nerve Stimulation. pp 1-10 in: Joel B. Myklebust, ed. Neuralstimulation (Volume 2). Boca Raton, Fla. CRC Press 1985; WALSH D M, LoweA S, McCormack K. Willer J-C, Baxter G D, Allen J M. Transcutaneouselectrical nerve stimulation: effect on peripheral nerve conduction,mechanical pain threshold, and tactile threshold in humans. Arch PhysMed Rehabil 79(1998):1051-1058; J A CAMPBELL. A critical appraisal ofthe electrical output characteristics of ten transcutaneous nervestimulators. Clin. phys. Physiol. Meas. 3(2, 1982): 141-150; U.S. Pat.No. 3,817,254, entitled Transcutaneous stimulator and stimulationmethod, to Maurer; U.S. Pat. No. 4,324,253, entitled Transcutaneous paincontrol and/or muscle stimulating apparatus, to Greene et al; U.S. Pat.No. 4,503,863, entitled Method and apparatus for transcutaneouselectrical stimulation, to Katims; U.S. Pat. No. 5,052,391, entitledHigh frequency high intensity transcutaneous electrical nerve stimulatorand method of treatment, to Silberstone et al; U.S. Pat. No. 6,351,674,entitled Method for inducing electroanesthesia using high frequency,high intensity transcutaneous electrical nerve stimulation, toSilverstone].

As TENS was being developed to treat pain, non-invasive electricalstimulation using surface electrodes was simultaneously developed foradditional therapeutic or diagnostic purposes, which are knowncollectively as electrotherapy. Neuromuscular electrical stimulation(NMES) stimulates normally innervated muscle in an effort to augmentstrength and endurance of normal (e.g., athletic) or damaged (e.g.,spastic) muscle. Functional electrical stimulation (FES) is used toactivate nerves innervating muscle affected by paralysis resulting fromspinal cord injury, head injury, stroke and other neurologicaldisorders, or muscle affected by foot drop and gait disorders. FES isalso used to stimulate muscle as an orthotic substitute, e.g., replace abrace or support in scoliosis management. Another application of surfaceelectrical stimulation is chest-to-back stimulation of tissue, such asemergency defibrillation and cardiac pacing. Surface electricalstimulation has also been used to repair tissue, by increasingcirculation through vasodilation, by controlling edema, by healingwounds, and by inducing bone growth. Surface electrical stimulation isalso used for iontophoresis, in which electrical currents driveelectrically charged drugs or other ions into the skin, usually to treatinflammation and pain, arthritis, wounds or scars. Stimulation withsurface electrodes is also used to evoke a response for diagnosticpurposes, for example in peripheral nerve stimulation (PNS) thatevaluates the ability of motor and sensory nerves to conduct and producereflexes. Surface electrical stimulation is also used inelectroconvulsive therapy to treat psychiatric disorders;electroanesthesia, for example, to prevent pain from dental procedures;and electrotactile speech processing to convert sound into tactilesensation for the hearing impaired. All of the above-mentionedapplications of surface electrode stimulation are intended not to damagethe patient, but if higher currents are used with special electrodes,electrosurgery may be performed as a means to cut, coagulate, desiccate,or fulgurate tissue [Mark R. Prausnitz. The effects of electric currentapplied to skin: A review for transdermal drug delivery. Advanced DrugDelivery Reviews 18 (1996) 395-425].

Despite its attractiveness, non-invasive electrical stimulation of anerve is not always possible or practical. This is primarily because thecurrent state of the art may not be able to stimulate a deep nerveselectively or without producing excessive pain, since the stimulationmay unintentionally stimulate nerves other than the nerve of interest,including nerves that cause pain. For this reason, forms of electricalstimulation other than TENS may be best suited for the treatment ofparticular types of pain [Paul F. WHITE, Shitong Li and Jen W. Chiu.Electroanalgesia: Its Role in Acute and Chronic Pain Management. AnesthAnalg 92(2001):505-13].

For some other electrotherapeutic applications, it has also beendifficult to perform non-invasive stimulation of a nerve, in lieu ofstimulating that nerve invasively. The therapies most relevant to thepresent invention involve electrical stimulation of the vagus nerve inthe neck, in order to treat epilepsy, depression, and other medicalconditions. For these therapies, the left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there, then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al and U.S.Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders bynerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009) 1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev (2005) 29:493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp.1-4].

When it is desired to avoid the surgical implantation of an electrode,vagal nerve stimulation (VNS) may be performed less invasively bypositioning one or more electrodes in the esophagus, trachea, or jugularvein, but with one electrode positioned on the surface of the body [U.S.Pat. No. 7,340,299, entitled Methods of indirectly stimulating the vagusnerve to achieve controlled asystole, to PUSKAS; and U.S. Pat. No.7,869,884, entitled Non-surgical device and methods for trans-esophagealvagus nerve stimulation, to SCOTT et al]. Despite their advantage asbeing non-surgical, such methods nevertheless exhibit otherdisadvantages associated with invasive procedures.

In other patents, non-invasive VNS is disclosed, but at a location otherthan in the neck [e.g., U.S. Pat. No. 4,865,048, entitled Method andapparatus for drug free neurostimulation, to ECKERSON; U.S. Pat. No.6,609,025 entitled Treatment of obesity by bilateral sub-diaphragmaticnerve stimulation to BARRETT et al; U.S. Pat. No. 5,458,625, entitledTranscutaneous nerve stimulation device and method for using same, toKENDALL; U.S. Pat. No. 7,386,347, entitled Electric stimulator foralpha-wave derivation, to Chung et al.; U.S. Pat. No. 7,797,042,entitled Device for applying a transcutaneous stimulus or fortranscutaneous measuring of a parameter, to Dietrich et al.; patentapplication US2010/0057154, entitled Device and Method for theTransdermal Stimulation of a Nerve of the Human Body, to Dietrich et al;US2006/0122675, entitled Stimulator for auricular branch of vagus nerve,to Libbus et al; US2008/0288016, entitled Systems and Methods forStimulating Neural Targets, to Amurthur et al]. However, because suchnon-invasive VNS occurs at a location other than the neck, it is notdirectly comparable to invasive VNS in the neck, for which therapeuticresults are well-documented. Among other patents and patentapplications, non-invasive VNS is sometimes mentioned along withinvasive VNS methods, but without addressing the problem ofunintentional stimulation of nerves other than the vagus nerve,particularly nerves that cause pain [e.g., US20080208266, entitledSystem and Method for Treating Nausea and Vomiting by Vagus NerveStimulation, to LESSER et al]. Other patents are vague as to hownon-invasive electrical stimulation in the vicinity of the vagus nervein the neck is to be accomplished [e.g., U.S. Pat. No. 7,499,747,entitled External baroreflex activation, to KIEVAL et al].

In view of the foregoing background, there is a long-felt but unsolvedneed to stimulate the vagus nerve electrically in the neck, totallynon-invasively, selectively, and essentially without producing pain. Ascompared with what would have been experienced by a patient undergoingnon-invasive stimulation with conventional TENS methods, the vagal nervestimulator should produce relatively little pain for a given depth ofstimulus penetration. Or conversely, for a given amount of pain ordiscomfort on the part of the patient (e.g., the threshold at which suchdiscomfort or pain begins), an objective of the present invention is toachieve a greater depth of penetration of the stimulus under the skin.Furthermore, an objective is not to stimulate other nerves and musclethat lie near the vagus nerve in the neck, but to nevertheless tostimulate the vagus nerve to achieve therapeutic results.

SUMMARY OF THE INVENTION

In one aspect of the invention, devices and methods are described toproduce therapeutic effects in a patient by utilizing an energy sourcethat transmits energy non-invasively to nervous tissue. In particular,the disclosed devices can transmit energy to, or in close proximity to,a vagus nerve in the neck of the patient, in order to temporarilystimulate, block and/or modulate electrophysiological signals in thatnerve. The methods that are disclosed herein comprise stimulating thevagus nerve with particular stimulation waveform parameters, preferablyusing the nerve stimulator devices that are also described herein.

In one aspect of the invention, a novel stimulator device is used tomodulate electrical activity of a vagus nerve or other nerves or tissue.The stimulator comprises a source of electrical power and one or moreremote electrodes that are configured to stimulate a deep nerve relativeto the nerve axis. The device also comprises continuous electricallyconducting media with which the electrodes are in contact. Theconducting medium is also in contact with an interface element thatmakes physical contact with the patient's skin. The interface elementmay be electrically insulating (dielectric) material, such as a sheet ofMylar, in which case electrical coupling of the device to the patient iscapacitive. In other embodiments, the interface element is electricallyconducting material, such as an electrically conducting or permeablemembrane, in which case electrical coupling of the device to the patientis ohmic. The interface element may have a shape that conforms to thecontour of a target body surface of a patient when the medium is appliedto the target body surface.

In another aspect of the invention, a novel stimulator device is used tomodulate electrical activity of a vagus nerve or other nerves or tissue.The stimulator comprises a source of electrical power and one or moreelectrodes that are configured to stimulate a deep nerve relative to thenerve axis. The device also comprises continuous electrically conductingmedia within which the electrode(s) are in contact. The conducting mediaprovides electrically communication between the electrode(s) and thepatient's tissue such that the electrode(s) are not in direct contactwith the tissue. The conducting medium preferably has a shape thatconforms to the contour of a target body surface of a patient when themedium is applied to the target body surface

For the present medical applications, the device is ordinarily appliedto the patient's neck. In a preferred embodiment of the invention, thestimulator comprises two electrodes that lie side-by-side withinseparate stimulator heads, wherein the electrodes are separated byelectrically insulating material. Each electrode and the patient's skinare in continuous contact with an electrically conducting medium thatextends from the interface element of the stimulator to the electrode.The interface element also contacts the patient's skin when the deviceis in operation. The conducting media for different electrodes are alsoseparated by electrically insulating material.

The source of power supplies a pulse of electric charge to theelectrodes, such that the electrodes produce an electric current and/oran electric field within the patient. The stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m and anelectrical field gradient of greater than 2 V/m/mm.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of 0 to 30 volts. The current is passedthrough the electrodes in bursts of pulses. There may be 0 to 30 pulsesper burst, preferably about 4 to 10 pulses and more preferably fivepulses. Each pulse within a burst has a duration of 20 to 1000microseconds, preferably 100-400 microseconds and more preferably about200 microseconds. A burst followed by a silent inter-burst intervalrepeats at 1 to 5000 bursts per second (bps), preferably at 15-50 bps.The preferred shape of each pulse is a full sinusoidal wave. Thepreferred stimulator shapes an elongated electric field of effect thatcan be oriented parallel to a long nerve, such as a vagus nerve in thepatient's neck. By selecting a suitable waveform to stimulate the nerve,along with suitable parameters such as current, voltage, pulse width,pulses per burst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves thatproduce pain.

Teachings of the present invention demonstrate how the disclosednon-invasive stimulators may be positioned and used against bodysurfaces, particularly at a location on the patient's neck under which avagus nerve is situated. Those teachings also describe the production ofcertain beneficial, therapeutic effects in a patient. However, it shouldbe understood that application of the methods and devices is not limitedto the examples that are given.

The novel systems, devices and methods for treating conditions using thedisclosed stimulator or other non-invasive stimulation devices are morecompletely described in the following detailed description of theinvention, with reference to the drawings provided herewith, and inclaims appended hereto. Other aspects, features, advantages, etc. willbecome apparent to one skilled in the art when the description of theinvention herein is taken in conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 is a schematic view of a nerve or tissue modulating deviceaccording to the present invention, which supplies controlled pulses ofelectrical current to electrodes that are continuously in contact with avolume filled with electrically conducting material.

FIG. 2 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulses that are applied to a portion orportions of a nerve, in accordance with an embodiment of the presentinvention.

FIG. 3 illustrates a dual-electrode stimulator according to anembodiment of the present invention, which is shown to house thestimulator's electrodes and electronic components.

FIG. 4 illustrates preferred and alternate embodiments of the head ofthe dual-electrode stimulator that is shown in FIG. 3.

FIG. 5 illustrates an alternate embodiment of the dual-electrodestimulator.

FIG. 6 illustrates the approximate position of the housing of thedual-electrode stimulator according one embodiment of the presentinvention, when the electrodes used to stimulate the vagus nerve in theneck of a patient.

FIG. 7 illustrates the housing of the dual-electrode stimulatoraccording one embodiment of the present invention, as the electrodes arepositioned to stimulate the vagus nerve in a patient's neck, is appliedto the surface of the neck in the vicinity of the identified anatomicalstructures.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, energy is transmitted non-invasively to apatient. The invention is particularly useful for producing appliedelectrical impulses that interact with the signals of one or more nervesto achieve a therapeutic result. In particular, the present disclosuredescribes devices and methods to stimulate a vagus nerve non-invasivelyat a location on the patient's neck.

There is a long-felt but unsolved need to stimulate the vagus nerveelectrically in the neck, totally non-invasively, selectively, andessentially without producing pain. As described below, this isevidenced by the failure of others to solve the problem that is solvedby the present invention, such that investigators abandoned the attemptto non-invasively stimulate electrically in the neck, in favor ofstimulating the vagus nerve at other anatomical locations, or in favorof stimulating the vagus nerve non-electrically. Japanese patentapplication JP2009233024A with a filing date of Mar. 26, 2008, entitledVagus Nerve Stimulation System, to Fukui YOSHIHITO, is concerned withstimulation of the vagus nerve on the surface of the neck to controlheart rate, rather than epilepsy, depression, or other infirmities thatvagal nerve stimulation (VNS) is ordinarily intended to treat.Nevertheless, the approach that is taken by Yoshihito illustrates thedifficulties encountered with non-invasive electrical stimulation thevagus nerve. Yoshihito notes that because electrical stimulation on thesurface of the neck may co-stimulate the phrenic nerve that is involvedwith the control of respiration, the patient hiccups and does notbreathe normally, resulting in “a patient sense of incongruity anddispleasure.” Yoshihito's proposed solution to the problem is tomodulate the timing and intensity of the electrical stimulation at theneck as a function of the respiratory phase, in such a way that theundesirable respiratory effects are minimized. Thus, Yoshihito'sapproach is to compensate for non-selective nerve stimulation, ratherthan find a way to stimulate the vagus nerve selectively. However, suchcompensatory modulation might also prevent the stimulation fromachieving a beneficial effect in treating epilepsy, depression, andother infirmities that are ordinarily treated with VNS. Furthermore,Yoshihito does not address the problem of pain in the vicinity of thestimulation electrodes. Similar issues could conceivably arise inconnection with possible co-stimulation of the carotid sinus nerve[Ingrid J. M. Scheffers, Abraham A. Kroon, Peter W. de Leeuw. CarotidBaroreflex Activation: Past, Present, and Future. Curr Hypertens Rep12(2010):61-66]. Side effects due to co-activation of muscle that iscontrolled by the vagus nerve itself may also occur, which exemplifyanother type of non-selective stimulation [M Tosato, K Yoshida, E Toftand J J Struijk. Quasi-trapezoidal pulses to selectively block theactivation of intrinsic laryngeal muscles during vagal nervestimulation. J. Neural Eng. 4 (2007): 205-212].

One circumvention of the problem that the present invention solves is tonon-invasively stimulate the vagus nerve at an anatomical location otherthan the neck, where the nerve lies closer to the skin. A preferredalternate location is in or around the ear (tragus, meatus and/orconcha) although other locations have been proposed [Manuel L. KARELL.TENS in the Treatment of Heroin Dependency. The Western Journal ofMedicine 125 (5, 1976):397-398; Enrique C. G. VENTUREYRA. Transcutaneousvagus nerve stimulation for partial onset seizure therapy. A newconcept. Child's Nery Syst 16 (2000):101-102; T. KRAUS, K. Hosl, O.Kiess, A. Schanze, J. Kornhuber, C. Forster. BOLD fMRI deactivation oflimbic and temporal brain structures and mood enhancing effect bytranscutaneous vagus nerve stimulation. J Neural Transm 114 (2007):1485-1493; POLAK T, Markulin F, Ehlis A C, Langer J B, Ringel T M,Fallgatter A J. Far field potentials from brain stem aftertranscutaneous vagus nerve stimulation: optimization of stimulation andrecording parameters. J Neural Transm 116(10, 2009):1237-1242; U.S. Pat.No. 5,458,625, entitled Transcutaneous nerve stimulation device andmethod for using same, to KENDALL; U.S. Pat. No. 7,797,042, entitledDevice for applying a transcutaneous stimulus or for transcutaneousmeasuring of a parameter, to Dietrich et al.; patent applicationUS2010/0057154, entitled Device and Method for the TransdermalStimulation of a Nerve of the Human Body, to Dietrich et al; See alsothe non-invasive methods and devices that Applicant disclosed incommonly assigned co-pending U.S. patent application Ser. No. 12/859,568entitled Non-invasive Treatment of Bronchial Constriction, to SIMON].However, it is not certain that stimulation in this minor branch of thevagus nerve will have the same effect as stimulation of a main vagusnerve in the neck, where VNS electrodes are ordinarily implanted, andfor which VNS therapeutic procedures produce well-documented results.

Another circumvention of the problem is to substitute electricalstimulation of the vagus nerve in the neck with some other form ofstimulation. For example, mechanical stimulation of the vagus nerve onthe neck has been proposed as an alternative to electrical stimulation[Jared M. HUSTON, Margot Gallowitsch-Puerta, Mahendar Ochani, KantaOchani, Renqi Yuan, Mauricio Rosas-Ballina, Mala Ashok, Richard S.Goldstein, Sangeeta Chavan, Valentin A. Pavlov, Christine N. Metz, HuanYang, Christopher J. Czura, Haichao Wang, Kevin J. Tracey.Transcutaneous vagus nerve stimulation reduces serum high mobility groupbox 1 levels and improves survival in murine sepsis Crit Care Med 35(12, 2007):2762-2768; Artur BAUHOFER and Alexander Torossian. Mechanicalvagus nerve stimulation—A new adjunct in sepsis prophylaxis andtreatment? Crit Care Med 35 (12, 2007):2868-2869; Hendrik SCHMIDT,Ursula Muller-Werdan, Karl Werdan. Assessment of vagal activity duringtranscutaneous vagus nerve stimulation in mice. Crit Care Med 36 (6,2008):1990; see also the non-invasive methods and devices that Applicantdisclosed in commonly assigned co-pending U.S. patent application Ser.No. 12/859,568, entitled Non-invasive Treatment of BronchialConstriction, to SIMON]. However, such mechanical VNS has only beenperformed in animal models, and there is no evidence that suchmechanical VNS would be functionally equivalent to electrical VNS.

Another circumvention of the problem is to use magnetic rather thanpurely electrical stimulation of the vagus nerve in the neck [Q. AZIZ etal. Magnetic Stimulation of Efferent Neural Pathways to the HumanOesophagus. Gut 33: S53-S70 (Poster Session F218) (1992); AZIZ, Q., J.C. Rothwell, J. Barlow, A. Hobson, S. Alani, J. Bancewicz, and D. G.Thompson. Esophageal myoelectric responses to magnetic stimulation ofthe human cortex and the extracranial vagus nerve. Am. J. Physiol. 267(Gastrointest. Liver Physiol. 30): G827-G835, 1994; Shaheen HAMDY, QasimAziz, John C. Rothwell, Anthony Hobson, Josephine Barlow, and David G.Thompson. Cranial nerve modulation of human cortical swallowing motorpathways. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35):G802-G808, 1997; Shaheen HAMDY, John C. Rothwell, Qasim Aziz, Krishna D.Singh, and David G. Thompson. Long-term reorganization of human motorcortex driven by short-term sensory stimulation. Nature Neuroscience 1(issue 1, May 1998):64-68; A. SHAFIK. Functional magnetic stimulation ofthe vagus nerve enhances colonic transit time in healthy volunteers.Tech Coloproctol (1999) 3:123-12; see also the non-invasive methods anddevices that Applicant disclosed in co-pending U.S. patent applicationSer. No. 12/859,568, entitled Non-invasive Treatment of BronchialConstriction, to SIMON, as well as co-pending U.S. patent applicationSer. No. 12/964,050, entitled Magnetic Stimulation Devices and Methodsof Therapy, to SIMON et al]. Magnetic stimulation might functionallyapproximate electrical stimulation. However, magnetic stimulation hasthe disadvantage that it ordinarily requires complex and expensiveequipment, and the duration of stimulation may be limited by overheatingof the magnetic stimulator. Furthermore, in some cases, magneticstimulation in the neck might also inadvertently stimulate nerves otherthan the vagus nerve, such as the phrenic nerve [SIMILOWSKI, T., B.Fleury, S. Launois, H. P. Cathala, P. Bouche, and J. P. Derenne.Cervical magnetic stimulation: a new painless method for bilateralphrenic nerve stimulation in conscious humans. J. Appl. Physiol. 67(4):1311-1318, 1989; Gerrard F. RAFFERTY, Anne Greenough, Terezia Manczur,Michael I. Polkey, M. Lou Harris, Nigel D. Heaton, Mohamed Rela, andJohn Moxham. Magnetic phrenic nerve stimulation to assess diaphragmfunction in children following liver transplantation. Pediatr Crit CareMed 2001, 2:122-126; W. D-C. MAN, J. Moxham, and M. I. Polkey. Magneticstimulation for the measurement of respiratory and skeletal musclefunction. Eur Respir J 2004; 24: 846-860]. Furthermore, magneticstimulation may also stimulate nerves that cause pain. Other stimulatorsthat make use of magnetic fields might also be used, but they too arecomplex and expensive and may share other disadvantages with moreconventional magnetic stimulators [U.S. Pat. No. 7,699,768, entitledDevice and method for non-invasive, localized neural stimulationutilizing hall effect phenomenon, to Kishawi et al].

Transcutaneous electrical stimulation (as well as magnetic stimulation)can be unpleasant or painful, in the experience of patients that undergosuch procedures. The quality of sensation caused by stimulation dependsstrongly on current and frequency, such that currents barely greaterthan the perception threshold generally cause painless sensationsdescribed as tingle, itch, vibration, buzz, touch, pressure, or pinch,but higher currents can cause sharp or burning pain. As the depth ofpenetration of the stimulus under the skin is increased (e.g., to deepernerves such as the vagus nerve), any pain will generally begin orincrease. Strategies to reduce the pain include: use of anestheticsplaced on or injected into the skin near the stimulation and placementof foam pads on the skin at the site of stimulation [Jeffrey J.BORCKARDT, Arthur R. Smith, Kelby Hutcheson, Kevin Johnson, Ziad Nahas,Berry Anderson, M. Bret Schneider, Scott T. Reeves, and Mark S. George.Reducing Pain and Unpleasantness During Repetitive Transcranial MagneticStimulation. Journal of ECT 2006; 22:259-264], use of nerve blockades[V. HAKKINEN, H. Eskola, A. Yli-Hankala, T. Nurmikko and S. Kolehmainen.Which structures are sensitive to painful transcranial stimulation?Electromyogr. clin. Neurophysiol. 1995, 35:377-383], the use of veryshort stimulation pulses [V. SUIHKO. Modelling the response of scalpsensory receptors to transcranial electrical stimulation. Med. Biol.Eng. Comput., 2002, 40, 395-401], decreasing current density byincreasing electrode size [Kristof VERHOEVEN and J. Gert van Dijk.Decreasing pain in electrical nerve stimulation. ClinicalNeurophysiology 117 (2006) 972-978], using a high impedance electrode[N. SHA, L. P. J. Kenney, B. W. Heller, A. T. Barker, D. Howard and W.Wang. The effect of the impedance of a thin hydrogel electrode onsensation during functional electrical stimulation. Medical Engineering& Physics 30 (2008): 739-746] and providing patients with the amount ofinformation that suits their personalities [Anthony DELITTO, Michael JStrube, Arthur D Shulman, Scott D Minor. A Study of Discomfort withElectrical Stimulation. Phys. Ther. 1992; 72:410-424]. U.S. Pat. No.7,614,996, entitled Reducing discomfort caused by electricalstimulation, to RIEHL discloses the application of a secondary stimulusto counteract what would otherwise be an uncomfortable primary stimulus.Other methods of reducing pain are intended to be used with invasivenerve stimulation [U.S. Pat. No. 7,904,176, entitled Techniques forreducing pain associated with nerve stimulation, to Ben-Ezra et al].

Additional considerations related to pain resulting from the stimulationare as follows. When stimulation is repeated over the course of multiplesessions, patients may adapt to the pain and exhibit progressively lessdiscomfort. Patients may be heterogeneous with respect to theirthreshold for pain caused by stimulation, including heterogeneityrelated to gender and age. Electrical properties of an individual's skinvary from day to day and may be affected by cleaning, abrasion, and theapplication of various electrode gels and pastes. Skin properties mayalso be affected by the stimulation itself, as a function of theduration of stimulation, the recovery time between stimulation sessions,the transdermal voltage, the current density, and the power density. Theapplication of multiple electrical pulses can result in differentperception or pain thresholds and levels of sensation, depending on thespacing and rate at which pulses are applied. The separation distancebetween two electrodes determines whether sensations from the electrodesare separate, overlap, or merge. The limit for tolerable sensation issometimes said to correspond to a current density of 0.5 mA/cm², but inreality the functional relationship between pain and current density isvery complicated. Maximum local current density may be more important inproducing pain than average current density, and local current densitygenerally varies under an electrode, e.g., with greater currentdensities along edges of the electrode or at “hot spots.” Furthermore,pain thresholds can have a thermal and/or electrochemical component, aswell as a current density component. Pulse frequency plays a significantrole in the perception of pain, with muscle contraction being involvedat some frequencies and not others, and with the spatial extent of thepain sensation also being a function of frequency. The sensation is alsoa function of the waveform (square-wave, sinusoidal, trapezoidal, etc.),especially if pulses are less than a millisecond in duration [Mark R.PRAUSNITZ. The effects of electric current applied to skin: A review fortransdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996):395-425].

Considering that there are so many variables that may influence thelikelihood of pain during non-invasive electrical stimulation (detailedstimulus waveform, frequency, current density, electrode type andgeometry, skin preparation, etc.), considering that these same variablesmust be simultaneously selected in order to independently produce adesired therapeutic outcome by vagal nerve stimulation, and consideringthat one also wishes to selectively stimulate the vagus nerve (e.g,avoid stimulating the phrenic nerve), it is understandable that prior tothe present disclosure, no one has described devices and methods forstimulating the vagus nerve electrically in the neck, totallynon-invasively, selectively, and without causing substantial pain.

Applicant discovered the disclosed devices and methods in the course ofexperimentation with a magnetic stimulation device that was disclosed inApplicant's commonly assigned co-pending U.S. patent application Ser.No. 12/964,050, entitled Magnetic Stimulation Devices and Methods ofTherapy, to SIMON et al. That stimulator used a magnetic coil, embeddedin a safe and practical conducting medium that was in direct contactwith arbitrarily-oriented patient skin, which had not been described inits closest art [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph. D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999. (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)]. Such a design, which isadapted herein for use with surface electrodes, makes it possible toshape the electric field that is used to selectively stimulate a deepnerve such as a vagus nerve in the neck. Furthermore, the designproduces significantly less pain or discomfort (if any) to a patientthan stimulator devices that are currently known in the art. Conversely,for a given amount of pain or discomfort on the part of the patient(e.g., the threshold at which such discomfort or pain begins), thedesign achieves a greater depth of penetration of the stimulus under theskin.

FIG. 1 is a schematic diagram of a nerve stimulating/modulating device300 for delivering impulses of energy to nerves for the treatment ofmedical conditions. As shown, device 300 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and electrodes 340 coupled via wires345 to impulse generator 310.

Although a pair of electrodes 340 is shown in FIG. 1, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 1represent all electrodes of the device collectively.

The item labeled in FIG. 1 as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asshown in the preferred embodiment, the medium is also deformable suchthat it is form-fitting when applied to the surface of the body. Thus,the sinuousness or curvature shown at the outer surface of theelectrically conducting medium 350 corresponds also to sinuousness orcurvature on the surface of the body, against which the conductingmedium 350 is applied, so as to make the medium and body surfacecontiguous. As described below in connection with a preferredembodiment, the volume 350 is electrically connected to the patient at atarget skin surface in order to shape the current density passed throughan electrode 340 that is needed to accomplish stimulation of thepatient's nerve or tissue. As also described below in connection withexemplary embodiments of the invention, the conducting medium in whichthe electrode 340 is embedded need not completely surround an electrode.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's electrodes. The signals are selected tobe suitable for amelioration of a particular medical condition, when thesignals are applied non-invasively to a target nerve or tissue via theelectrodes 340. It is noted that nerve stimulating/modulating device 300may be referred to by its function as a pulse generator. Patentapplication publications US2005/0075701 and US2005/0075702, both toSHAFER, both of which are incorporated herein by reference, relating tostimulation of neurons of the sympathetic nervous system to attenuate animmune response, contain descriptions of pulse generators that may beapplicable to the present invention. By way of example, a pulsegenerator 300 is also commercially available, such as Agilent 33522AFunction/Arbitrary Waveform Generator, Agilent Technologies, Inc., 5301Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas any externally supplied physiological signals, analog-to-digitalconverters for digitizing externally supplied analog signals,communication devices for the transmission and receipt of data to andfrom external devices such as printers and modems that comprise part ofthe system, hardware for generating the display of information onmonitors that comprise part of the system, and busses to interconnectthe above-mentioned components. Thus, the user may operate the system bytyping instructions for the control unit 330 at a device such as akeyboard and view the results on a device such as the system's computermonitor, or direct the results to a printer, modem, and/or storage disk.Control of the system may be based upon feedback measured fromexternally supplied physiological or environmental signals.Alternatively, the control unit 330 may have a compact and simplestructure, for example, wherein the user may operate the system usingonly an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes, as well as the spatial distribution ofthe electric field that is produced by the electrodes. The rise time andpeak energy are governed by the electrical characteristics of thestimulator and electrodes, as well as by the anatomy of the region ofcurrent flow within the patient. In one embodiment of the invention,pulse parameters are set in such as way as to account for the detailedanatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,Robert Szmurto, Przemystaw Ptonecki, Jacek Starzyński, StanislawWincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 2A illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe electrodes. As shown, a suitable electrical voltage/current profile400 for the blocking and/or modulating impulse 410 to the portion orportions of a nerve may be achieved using pulse generator 310. In apreferred embodiment, the pulse generator 310 may be implemented using apower source 320 and a control unit 330 having, for instance, aprocessor, a clock, a memory, etc., to produce a pulse train 420 to theelectrodes 340 that deliver the stimulating, blocking and/or modulatingimpulse 410 to the nerve. Nerve stimulating/modulating device 300 may beexternally powered and/or recharged may have its own power source 320.The parameters of the modulation signal 400, such as the frequency,amplitude, duty cycle, pulse width, pulse shape, etc., are preferablyprogrammable. An external communication device may modify the pulsegenerator programming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes,the device disclosed in patent publication No. US2005/0216062 (theentire disclosure of which is incorporated herein by reference) may beemployed. That patent publication discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type the user wishes, who can then observe the effectof this signal on a substance being treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example, the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 50 Hz, more preferably around 25Hz. The modulation signal may have a pulse width selected to influencethe therapeutic result, such as about 20 microseconds or greater, suchas about 20 microseconds to about 1000 microseconds. For example, theelectric field induced by the device within tissue in the vicinity of anerve is 10 to 600 V/m, preferably around 300 V/m. The gradient of theelectric field may be greater than 2 V/m/mm. More generally, thestimulation device produces an electric field in the vicinity of thenerve that is sufficient to cause the nerve to depolarize and reach athreshold for action potential propagation, which is approximately 8 V/mat 1000 Hz.

An objective of the disclosed stimulator is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode configuration, and nervefiber selectivity may be achieved in part through the design of thestimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement or overlap others that are used to achieveselective nerve stimulation, such as the use of local anesthetic,application of pressure, inducement of ischemia, cooling, use ofultrasound, graded increases in stimulus intensity, exploiting theabsolute refractory period of axons, and the application of stimulusblocks [John E. SWETT and Charles M. Bourassa. Electrical stimulation ofperipheral nerve. In: Electrical Stimulation Research Techniques,Michael M. Patterson and Raymond P. Kesner, eds. Academic Press. (NewYork, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for vagalnerve stimulation (VNS) has been highly empirical, in which theparameters are varied about some initially successful set of parameters,in an effort to find an improved set of parameters for each patient. Amore efficient approach to selecting stimulation parameters might be toselect a stimulation waveform that mimics electrical activity in theregions of the brain that one is attempting stimulate indirectly, in aneffort to entrain the naturally occurring electrical waveform, assuggested in U.S. Pat. No. 6,234,953, entitled Electrotherapy deviceusing low frequency magnetic pulses, to THOMAS et al. and applicationnumber US20090299435, entitled Systems and methods for enhancing oraffecting neural stimulation efficiency and/or efficacy, to GLINER etal. One may also vary stimulation parameters iteratively, in search ofan optimal setting [U.S. Pat. No. 7,869,885, entitled Thresholdoptimization for tissue stimulation therapy, to Begnaud, et al].However, some VNS stimulation waveforms, such as those described herein,are discovered by trial and error, and then deliberately improved upon.

Invasive vagal nerve stimulation typically uses square wave pulsesignals. The typical waveform parameter values for VNS therapy forepilepsy and depression are: a current between 1 and 2 mA, a frequencyof between 20 and 30 Hz, a pulse width of 250-500 microseconds, and aduty cycle of 10% (signal ON time of 30 s, and a signal OFF time to 5min). Output current is gradually increased from 0.25 mA to the maximumtolerable level (maximum, 3.5 mA), with typical therapeutic settingsranging from 1.0 to 1.5 mA. Greater output current is associated withincreased side effects, including voice alteration, cough, a feeling ofthroat tightening, and dyspnea. Frequency is typically 20 Hz indepression and 30 Hz in epilepsy. The therapy is adjusted in a gradual,systematic fashion to individualize therapy for each patient. To treatmigraine headaches, typical VNS parameters are a current of 0.25 to 1mA, a frequency of 30 Hz, a pulse width of 500 microseconds, and an ‘ON’time of 30 s every 5 min. To treat migrane plus epilepsy, typicalparameters are 1.75 mA, a frequency of 20 Hz, a pulse width of 250microseconds, and ‘ON’ time of 7 s followed by an ‘OFF’ time of 12 s. Totreat mild to moderate Alzheimer's disease, typical VNS waveformparameters are: a current of 0.25 to 0.5 mA, a frequency of 20 Hz, apulse width of 500 microseconds, and an ‘ON’ time of 30 s every 5 min.[ANDREWS, A. J., 2003. Neuromodulation. I. Techniques-deep brainstimulation, vagus nerve stimulation, and transcranial magneticstimulation. Ann. N. Y. Acad. Sci. 993, 1-13; LABINER, D. M., Ahern, G.L., 2007. Vagus nerve stimulation therapy in depression and epilepsy:therapeutic parameter settings. Acta. Neurol. Scand. 115, 23-33; G. C.ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brain stimulation,vagal nerve stimulation and transcranial stimulation: An overview ofstimulation parameters and neurotransmitter release. Neuroscience andBiobehavioral Reviews 33 (2009) 1042-1060]. Applicant found that thesesquare waveforms are not ideal for non-invasive VNS stimulation as theyproduce excessive pain.

Prepulses and similar waveform modifications have been suggested asmethods to improve selectivity of vagus and other nerve stimulationwaveforms, but Applicant did not find them ideal [Aleksandra VUCKOVIC,Marco Tosato and Johannes J Struijk. A comparative study of threetechniques for diameter selective fiber activation in the vagal nerve:anodal block, depolarizing prepulses and slowly rising pulses. J. NeuralEng. 5 (2008): 275-286; Aleksandra VUCKOVIC, Nico J. M. Rijkhoff, andJohannes J. Struijk. Different Pulse Shapes to Obtain Small FiberSelective Activation by Anodal Blocking—A Simulation Study. IEEETransactions on Biomedical Engineering 51(5, 2004):698-706; KristianHENNINGS. Selective Electrical Stimulation of Peripheral Nerve Fibers:Accommodation Based Methods. Ph.D. Thesis, Center for Sensory-MotorInteraction, Aalborg University, Aalborg, Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive VNS stimulation [M. I.JOHNSON, C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesiceffects of different pulse patterns of transcutaneous electrical nervestimulation on cold-induced pain in normal subjects. Journal ofPsychosomatic Research 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340,entitled Stimulation design for neuromodulation, to De Ridder]. However,bursts of sinusoidal pulses are a preferred stimulation waveform, asshown in FIGS. 2B and 2C. As seen there, individual sinusoidal pulseshave a period of τ, and a burst consists of N such pulses. This isfollowed by a period with no signal (the inter-burst period). Thepattern of a burst plus followed by silent inter-burst period repeatsitself with a period of T. For example, the sinusoidal period τ may bebetween about 50 us to about 1 ms, preferably between about 100 us to400 us, and more preferably about 200 microseconds; the number of pulsesper burst (N) maybe be between about 2 to 20 pulses, preferably about 4to 10 pulses and more preferably 5 pulses; and the whole pattern ofburst followed by silent inter-burst period may have a period (T) ofabout 1 to 100 Hz, preferably about 10 to 35 Hz and more preferablyabout 25 Hz or 40000 microseconds (a much smaller value of T is shown inFIG. 2C to make the bursts discernable). Applicant is unaware of such awaveform having been used with vagal nerve stimulation, but a similarwaveform has been used to stimulate muscle as a means of increasingmuscle strength in elite athletes. However, for the muscle strengtheningapplication, the currents used (200 mA) may be very painful and twoorders of magnitude larger than what is disclosed herein for VNS.

When these exemplary values are used for T and τ, the waveform containssignificant Fourier components at higher frequencies ( 1/200microseconds=5000/sec), as compared with those contained intranscutaneous nerve stimulation waveforms, as currently practiced.Furthermore, the signal used for muscle strengthening may be other thansinusoidal (e.g., triangular), and the parameters τ, N, and T may alsobe dissimilar from the values exemplified above [A. DELITTO, M. Brown,M. J. Strube, S. J. Rose, and R. C. Lehman. Electrical stimulation ofthe quadriceps femoris in an elite weight lifter: a single subjectexperiment. Int J Sports Med 10(1989):187-191; Alex R WARD, NataliyaShkuratova. Russian Electrical Stimulation: The Early Experiments.Physical Therapy 82 (10, 2002): 1019-1030; Yocheved LAUFER and MichalElboim. Effect of Burst Frequency and Duration of Kilohertz-FrequencyAlternating Currents and of Low-Frequency Pulsed Currents on Strength ofContraction, Muscle Fatigue, and Perceived Discomfort. Physical Therapy88 (10, 2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. By way of example, the electric field shown in FIGS. 2Band 2C may have an E_(max) value of 17 V/m, which is sufficient tostimulate the vagus nerve but is significantly lower than the thresholdneeded to stimulate surrounding muscle.

In order to compare the stimulator that is disclosed herein withexisting electrodes and stimulators used for non-invasive electricalstimulation, it is useful to first summarize the relevant physics ofelectric fields and currents that are produced by the electrodes.According to Maxwell's equation (Ampere's law with Maxwell correction):∇×B=J+∈(∂E/∂t), where B is the magnetic field, J is the electricalcurrent density, E is the electric field, ∈ is the permittivity, and tis time [Richard P. FEYNMAN, Robert B. Leighton, and Matthew Sands. TheFeynman Lectures on Physics. Volume II. Addison-Wesley Publ. Co.(Reading Mass., 1964), page 15-15].

According to Faraday's law, ∇×E=−∂B/∂t. However, for present purposes,changes in the magnetic field B may be ignored, so ∇×E=0, and E maytherefore be obtained from the gradient of a scalar potential Φ: E=−∇Φ.In general, the scalar potential Φ and the electric field E arefunctions of position (r) and time (t).

The electrical current density J is also a function of position (r) andtime (t), and it is determined by the electric field and conductivity asfollows, where the conductivity σ is generally a tensor and a functionof position (r): J=σE=−σ∇Φ.

Because ∇·∇×B=0, Ampere's law with Maxwell's correction may be writtenas:

∇·J+∇·∈ (∂E/∂t)=0. If the current flows in material that is essentiallyunpolarizable (i.e., is presumed not to be a dielectric so that ∈=0),substitution of the expression for J into the above expression forAmpere's law gives −∇·(σ∇Φ)=0, which is a form of Laplace's equation. Ifthe conductivity of material in the device (or patient) is itself afunction of the electric field or potential, then the equation becomesnon-linear, which could exhibit multiple solutions, frequencymultiplication, and other such non-linear behavior. The equation hasbeen solved analytically for special electrode configurations, but formore general electrode configurations, it must be solved numerically[Petrus J. CILLIERS. Analysis of the current density distribution due tosurface electrode stimulation of the human body. Ph.D. Dissertation,Ohio State University, 1988. (UMI Microform Number: 8820270, UMICompany, Ann Arbor Mich.); Martin REICHEL, Teresa Breyer, Winfried Mayr,and Frank Rattay. Simulation of the Three-Dimensional Electrical Fieldin the Course of Functional Electrical Stimulation. Artificial Organs26(3, 2002):252-255; Cameron C. McINTYRE and Warren M. Grill. FiniteElement Analysis of the Current-Density and Electric Field Generated byMetal Microelectrodes. Annals of Biomedical Engineering 29 (2001):227-235; A. PATRICIU, T. P. DeMonte, M. L. G. Joy, J. J. Struijk.Investigation of current densities produced by surface electrodes usingfinite element modeling and current density imaging. Proceedings of the23rd Annual EMBS International Conference, Oct. 25-28, 2001, Istanbul,Turkey: 2403-2406; Yong H U, XB Xie, L Y Pang, X H Li K D K Luk. CurrentDensity Distribution Under Surface Electrode on Posterior Tibial NerveElectrical Stimulation. Proceedings of the 2005 IEEE Engineering inMedicine and Biology 27th Annual Conference Shanghai, China, Sep. 1-4,2005: 3650-3652]. The equation has also been solved numerically in orderto compare different electrode shapes and numbers [Abhishek DATTA, MagedElwassif, Fortunato Battaglia and Marom Bikson. Transcranial currentstimulation focality using disc and ring electrode configurations: FEManalysis. J. Neural Eng. 5 (2008) 163-174; Jay T. RUBENSTEIN, Francis A.Spelman, Mani Soma and Michael F. Suesserman. Current Density Profilesof Surface Mounted and Recessed Electrodes for Neural Prostheses. IEEETransactions on Biomedical Engineering BME-34 (11, 1987): 864-875; DavidA. KSIENSKI. A Minimum Profile Uniform Current Density Electrode. IEEETransactions on Biomedical Engineering 39 (7, 1992): 682-692; AndreasKUHN, Thierry Keller, Silvestro Micera, Manfred Morari. Array electrodedesign for transcutaneous electrical stimulation: A simulation study.Medical Engineering & Physics 31 (2009) 945-951]. The calculatedelectrical fields may be confirmed using measurements using a phantom[A. M. SAGI_DOLEV, D. Prutchi and R. H. Nathan. Three-dimensionalcurrent density distribution under surface stimulation electrodes. Med.and Biol. Eng. and Comput. 33(1995): 403-408].

If capacitive effects cannot be ignored, an additional term involvingthe time-derivative of the gradient of the potential appears in the moregeneral expression, as obtained by substituting the expressions for Jand E into the divergence of Ampere's law with Maxwell's correction:−∇·(σ∇Φ)−∇·(∈∇(∂Φ/∂t))=0

The permittivity ∈ is a function of position (r) and is generally atensor. It may result from properties of the body and may also be aproperty of the electrode design [L. A. GEDDES, M. Hinds and K. S.Foster. Stimulation with capacitor electrodes. Med. and Biol. Eng. andComput. 25(1987):359-360]. As a consequence of such a term, the waveformof the electrical potential at points within the body will generally bealtered relative to the waveform of the voltage signal(s) applied to theelectrode(s). Furthermore, if the permittivity of a material in thedevice itself (or patient) is a function of the electric field orpotential, then the equation becomes non-linear, which could exhibitmultiple solutions, frequency multiplication, and other such non-linearbehavior. This time-dependent equation has been solved numerically [KUHNA, Keller T. A 3D transient model for transcutaneous functionalelectrical stimulation. Proc. 10th Annual Conference of theInternational FES Society July 2005—Montreal, Canada: pp. 1-3; AndreasKUHN, Thierry Keller, Marc Lawrence, Manfred Morari. A model fortranscutaneous current stimulation: simulations and experiments. MedBiol Eng Comput 47(2009):279-289; N. FILIPOVIC, M. Nedeljkovic, A.Peulic. Finite Element Modeling of a Transient Functional ElectricalStimulation. Journal of the Serbian Society for Computational Mechanics1 (1, 2007):154-163; Todd A. KUIKEN, Nikolay S. Stoykov, Milica Popovic,Madeleine Lowery and Allen Taflove. Finite Element Modeling ofElectromagnetic Signal Propagation in a Phantom Arm. IEEE Transactionson Neural Systems and Rehabilitation Engineering 9 (4, 2001): 346-354].

In any case, Dirichlet (D) boundary conditions define voltage sources,and Neumann (N) boundary conditions describe the behavior of theelectric field at the crossover boundary from skin to air, as follows:N: ∂Φ=∂n=σ(r) and D: Φ=V(t)where n denotes the outward pointing normal vector, i.e., the vectororthogonal to the boundary curve; and V(t) denotes the voltage appliedto an electrode. Thus, no conduction current can flow across anair/conductor interface, so according to the interfacial boundaryconditions, the component of any current normal to the an air/conductorinterface must be zero. In constructing the above differential equationfor Φ as a function of time, the divergence of J is taken, whichsatisfies the continuity equation: ∇·J=−∂ρ/∂t, where ρ is the chargedensity. Conservation of charge requires that sides of this equationequal zero everywhere except at the surface of the electrode wherecharge is impressed upon the system (injected or received).

It is an objective of the present invention to shape an elongatedelectric field of effect that can be oriented parallel to a long nervesuch as the vagus nerve in the neck. The term “shape an electric field”as used herein means to create an electric field or its gradient that isgenerally not radially symmetric at a given depth of stimulation in thepatient, especially a field that is characterized as being elongated orfinger-like, and especially also a field in which the magnitude of thefield in some direction may exhibit more than one spatial maximum (i.e.may be bimodal or multimodal) such that the tissue between the maximamay contain an area across which current flow is restricted. Shaping ofthe electric field refers both to the circumscribing of regions withinwhich there is a significant electric field and to configuring thedirections of the electric field within those regions. Our inventiondoes so by configuring elements that are present within the equationsthat were summarized above, comprising (but not limited to) thefollowing exemplary configurations that may be used alone or incombination.

First, different contours or shapes of the electrodes affect ∇·J. Forexample, charge is impressed upon the system (injected or received)differently if an electode is curved versus flat, or if there are morethan two electrodes in the system.

Second, values of the voltage V(t) in the above boundary condition ismanipulated to shape the electric field. For example, if the devicecontains two pairs of electrodes that are perpendicular or at a variableangle with respect to one another, the waveform of the voltage acrossone pair of electrodes may be different than the waveform of the voltageacross the second pair, so that the superimposed electric fields thatthey produce may exhibit beat frequencies, as has been attempted withelectrode-based stimulators [U.S. Pat. No. 5,512,057, entitledInterferential stimulator for applying localized stimulation, to REISSet al.], and acoustic stimulators [U.S. Pat. No. 5,903,516, entitledAcoustic force generator for detection, imaging and informationtransmission using the beat signal of multiple intersecting sonic beams,to GREENLEAF et al].

Third, the scalar potential Φ in the above equation ∂Φ/∂n=σ(r) may bemanipulated to shape the electric field. For example, this isaccomplished by changing the boundaries of conductor/air (ornon-conductor) interfaces, thereby creating different boundaryconditions. For example, the conducting material may pass throughconducting apertures in an insulated mesh before contacting thepatient's skin, creating thereby an array of electric field maxima. Asanother example, an electrode may be disposed at the end of a long tubethat is filled with conducting material, or the electrode may besituated at the bottom of a curved cup that is filled with conductingmaterial. In those cases the dimensions of the tube or cup would affectthe resulting electric fields and currents.

Fourth, the conductivity σ (in the equation J=σE) may be variedspatially within the device by using two or more different conductingmaterials that are in contact with one another, for given boundaryconditions. The conductivity may also be varied by constructing someconducting material from a semiconductor, which allows for adjustment ofthe conductivity in space and in time by exposure of the semiconductorto agents to which they are sensitive, such as electric fields, light atparticular wavelengths, temperature, or some other environmentalvariable over which the user of the device has control. For the specialcase in which the semiconductor's conductivity may be made to approachzero, that would approximate the imposition of an interfacial boundarycondition as described in the previous paragraph.

Fifth, a dielectric material having a high permittivity E, such asMylar, neoprene, titanium dioxide, or strontium titanate, may be used inthe device, for example, in order to permit capacitative electricalcoupling to the patient's skin. Changing the permittivity in conjunctionalong with changing the waveform V(t) would especially affect operationof the device, because the permittivity appears in a term that is afunction of the time-derivative of the electric potential:∇·(∈∇(∂Φ/∂t)).

In configurations of the present invention, an electrode is situated ina container that is filled with conducting material. In one embodiment,the container contains holes so that the conducting material (e.g., aconducting gel) can make physical contact with the patient's skinthrough the holes. For example, the conducting medium 350 in FIG. 1 maycomprise a chamber surrounding the electrode, filled with a conductivegel that has the approximate viscosity and mechanical consistency of geldeodorant (e.g., Right Guard Clear Gel from Dial Corporation, 15501 N.Dial Boulevard, Scottsdale Ariz. 85260, one composition of whichcomprises aluminum chlorohydrate, sorbitol, propylene glycol,polydimethylsiloxanes Silicon oil, cyclomethicone, ethanol/SD Alcohol40, dimethicone copolyol, aluminum zirconium tetrachlorohydrex gly, andwater). The gel, which is less viscous than conventional electrode gel,is maintained in the chamber with a mesh of openings at the end wherethe device is to contact the patient's skin. The gel does not leak out,and it can be dispensed with a simple screw driven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient. Rather thanusing agar as the conducting medium, an electrode can instead be incontact with in a conducting solution such as 1-10% NaCl that alsocontacts an electrically conducting interface to the human tissue. Suchan interface is useful as it allows current to flow from the electrodeinto the tissue and supports the conducting medium, wherein the devicecan be completely sealed. Thus, the interface is material, interposedbetween the conducting medium and patient's skin, that allows theconducting medium (e.g., saline solution) to slowly leak through it,allowing current to flow to the skin. Several interfaces (351 in FIG. 1)are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13 pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.Another example is the KM10T hydrogel from Katecho Inc., 4020 GannettAve., Des Moines Iowa 50321.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the electrode and conducting solutionin from the tissue, yet allow current to pass.

The stimulator 340 in FIG. 1 shows two equivalent electrodes,side-by-side, wherein electrical current would pass through the twoelectrodes in opposite directions. Thus, the current will flow from oneelectrode, through the tissue and back through the other electrode,completing the circuit within the electrodes' conducting media that areseparated from one another. An advantage of using two equivalentelectrodes in this configuration is that this design will increase themagnitude of the electric field gradient between them, which is crucialfor exciting long, straight axons such as the vagus nerve in the neckand other deep peripheral nerves.

A preferred embodiment of the stimulator is shown in FIG. 3A. Across-sectional view of the stimulator along its long axis is shown inFIG. 3B. As shown, the stimulator (30) comprises two heads (31) and abody (32) that joins them. Each head (31) contains a stimulatingelectrode. The body of the stimulator (32) contains the electroniccomponents and battery (not shown) that are used to generate the signalsthat drive the electrodes, which are located behind the insulating board(33) that is shown in FIG. 3B. However, in other embodiments of theinvention, the electronic components that generate the signals that areapplied to the electrodes may be separate, but connected to theelectrode head (31) using wires. Furthermore, other embodiments of theinvention may contain a single such head or more than two heads.

Heads of the stimulator (31) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (34) that also serves as an on/off switch. A light(35) is illuminated when power is being supplied to the stimulator. Anoptional cap may be provided to cover each of the stimulator heads (31),to protect the device when not in use, to avoid accidental stimulation,and to prevent material within the head from leaking or drying. Thus, inthis embodiment of the invention, mechanical and electronic componentsof the stimulator (impulse generator, control unit, and power source)are compact, portable, and simple to operate.

Construction of different embodiments of the stimulator head is shown inmore detail in FIG. 4. Referring now to the exploded view shown in FIG.4A, the electrode head is assembled from a snap-on cap (41) that servesas a tambour for a dielectric or conducting membrane (42), a discwithout fenestration (43) or alternatively with fenestration (43′), thehead-cup (44), and the electrode which is also a screw (45). Twoembodiments of the disc (43) are shown. The preferred embodiment (43) isa solid, ordinarily uniformly conducting disc (e.g., metal such asstainless steel), which is possibly flexible in some embodiments. Thematerial for the conductive interface can generally be anybiocompatible, electrically conductive material that remains solid atbody temperatures and does not chemically react to water or conductivefluids, such as stainless steel, germanium, titanium and the like. Analternate embodiment of the disc (43′) is also shown, which is anon-conducting (e.g., plastic) aperture screen that permits electricalcurrent to pass through its apertures. The electrode (45, also 340 inFIG. 1) seen in each stimulator head has the shape of a screw that isflattened on its tip. Pointing of the tip would make the electrode moreof a point source, such that the above-mentioned equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditions.Completed assembly of the stimulator head is shown in FIG. 4B, whichalso shows how the head is attached to the body of the stimulator (47).

The membrane (42) ordinarily serves as the interface shown as 351 inFIG. 1. For example, the membrane (42) may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment shown in FIG. 4A,apertures of the alternate disc (43′) may be open, or they may beplugged with conducting material, for example, KM10T hydrogel fromKatecho Inc., 4020 Gannett Ave., Des Moines Iowa 50321. If the aperturesare so-plugged, and the membrane (42) is made of conducting material,the membrane becomes optional, and the plug serves as the interface 351shown in FIG. 1.

The head-cup (44) is filled with conducting material (350 in FIG. 1),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield N.J. 07004. The snap-on cap (41), aperturescreen disc (43′), head-cup (44) and body of the stimulator are made ofa non-conducting material, such as acrylonitrile butadiene styrene. Thedepth of the head-cup from its top surface to the electrode may bebetween one and six centimeters. The head-cup may have a differentcurvature than what is shown in FIG. 4, or it may be tubular or conicalor have some other inner surface geomety that will affect the Neumannboundary conditions.

The alternate embodiment of the stimulator head that is shown in FIG. 4Calso contains a snap-on cap (41), membrane (42) that is made of adielectric or a conducting material, the head-cup (44), and theelectrode which is also a screw (45). This alternate embodiment differsfrom the embodiment shown in FIGS. 4A and 4B in regard to the mechanicalsupport that is provided to the membrane (42). Whereas the disc (43) or(43′) had provided mechanical support to the membrane in the otherembodiment, in the alternate embodiment a reinforcing ring (40) isprovided to the membrane. That reinforcement ring rests onnon-conducting struts (49) that are placed in the head-cup (44), and anon-conducting strut-ring (48) is placed within notches in the struts(49) to hold the struts in place. An advantage of the alternateembodiment is that without a disc (43) or (43′), current flow may beless restricted through the membrane (42), especially if the membrane ismade of a conducting material. Furthermore, although the struts andstrut-ring are made of non-conducting material in this alternateembodiment, the design may be adapted to position additional electrodeor other conducting elements within the head-cup for other morespecialized configurations of the stimulator head, the inclusion ofwhich will influence the electric fields that are generated by thedevice. Completed assembly of the alternate stimulator head is shown inFIG. 4D, without showing its attachment to the body of the stimulator.In fact, it is possible to insert a lead under the head of the electrode(45), and many other methods of attaching the electrode to thesignal-generating electronics of the stimulator are known in the art.

If the membrane (42) is made of conducting materials, and the disc (43)in FIG. 4A is made of solid conducting materials such as stainlesssteel, the membrane becomes optional, and the disc serves as theinterface 351 shown in FIG. 1. Thus, an embodiment without the membraneis shown in FIGS. 4E and 4F. FIG. 4E shows that this version of thedevice comprises a solid (but possibly flexible in some embodiments)conducting disc that cannot absorb fluid (43), the non-conductingstimulator head (44) into or onto which the disc is placed, and theelectrode (45), which is also a screw. As seen in FIG. 4F, these itemsare assembled to become a sealed stimulator head that is attached to thebody of the stimulator (47). The disc (43) may screw into the stimulatorhead (44), it may be attached to the head with adhesive, or it may beattached by other methods that are known in the art. The chamber of thestimulator head-cup is filled with a conducting gel, fluid, or paste,and because the disc (43) and electrode (45) are tightly sealed againstthe stimulator head-cup (44), the conducting material within thestimulator head cannot leak out.

In a preferred embodiment of the present invention, the interface (351in FIG. 1, or 42 in FIG. 4) is made from a very thin material with ahigh dielectric constant, such as material used to make capacitors. Forexample, it may be Mylar having a submicron thickness (preferably in therange 0.5 to 1.5 microns) having a dielectric constant of about 3.Because one side of Mylar is slick, and the other side ismicroscopically rough, the present invention contemplates two differentconfigurations: one in which the slick side is oriented towards thepatient's skin, and the other in which the rough side is so-oriented.Thus, at stimulation Fourier frequencies of several kilohertz orgreater, the dielectric interface will capacitively couple the signalthrough itself, because it will have an impedance comparable to that ofthe skin. Thus, the dielectric interface will isolate the stimulator'selectrode from the tissue, yet allow current to pass. In a preferredembodiment of the present invention, non-invasive electrical stimulationof a nerve is accomplished essentially substantially capacitively, whichreduces the amount of ohmic stimulation, thereby reducing the sensationthe patient feels on the tissue surface. This would correspond to asituation, for example, in which at least 30%, preferably at least 50%,of the energy stimulating the nerve comes from capacitive couplingthrough the stimulator interface, rather than from ohmic coupling. Inother words, a substantial portion (e.g., 50%) of the voltage drop isacross the dielectric interface, while the remaining portion is throughthe tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to 5 microns (preferably about 1 micron) with as dielectricconstant of about 3. For a piezoelectric material like barium titanateor PZT (lead zirconate titanate), the thickness could be about 100-400microns (preferably about 200 microns or 0.2 mm) because the dielectricconstant is >1000.

In another embodiment, the interface comprises a fluid permeablematerial that allows for passage of current through the permeableportions of the material. In this embodiment, a conductive medium (suchas a gel) is preferably situated between the electrode(s) and thepermeable interface. The conductive medium provides a conductive pathwayfor electrons to pass through the permeable interface to the outersurface of the interface and to the patient's skin.

One of the novelties of the disclosed stimulating, non-invasivecapacitive stimulator (hereinafter referred to more generally as acapacitive electrode) arises in that it uses a low voltage (generallyless than 100 volt) power source, which is made possible by the use of asuitable stimulation waveform, such as the waveform that is disclosedherein (FIGS. 2B and 2C). In addition, the capacitive electrode allowsfor the use of an interface that provides a more adequate seal of theinterior of the device. The capacitive electrode may be used by applyinga small amount of conductive material (e.g., conductive gel as describedabove) to its outer surface. In some embodiments, it may also be used bycontacting dry skin, thereby avoiding the inconvenience of applying anelectrode gel, paste, or other electrolytic material to the patient'sskin and avoiding the problems associated with the drying of electrodepastes and gels. Such a dry electrode would be particularly suitable foruse with a patient who exhibits dermatitis after the electrode gel isplaced in contact with the skin [Ralph J. COSKEY. Contact dermatitiscaused by ECG electrode jelly. Arch Dermatol 113(1977): 839-840]. Thecapacitive electrode may also be used to contact skin that has beenwetted (e.g., with tap water or a more conventional electrolytematerial) to make the electrode-skin contact (here the dielectricconstant) more uniform [A L ALEXELONESCU, G Barbero, F C M Freire, and RMerletti. Effect of composition on the dielectric properties ofhydrogels for biomedical applications. Physiol. Meas. 31 (2010)S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the invention(low-voltage, non-invasive capacitive stimulation of a nerve), isprovided by KELLER and Kuhn, who review the previous high-voltagecapacitive stimulating electrode of GEDDES et al and write that“Capacitive stimulation would be a preferred way of activating musclenerves and fibers, when the inherent danger of high voltage breakdownsof the dielectric material can be eliminated. Goal of future researchcould be the development of improved and ultra-thin dielectric foils,such that the high stimulation voltage can be lowered.” [L. A. GEDDES,M. Hinds, and K. S. Foster. Stimulation with capacitor electrodes.Medical and Biological Engineering and Computing 25(1987): 359-360;Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45, on page 39]. It is understood that in theUnited States, according to the 2005 National Electrical Code, highvoltage is any voltage over 600 V. U.S. Pat. No. 3,077,884, entitledElectro-physiotherapy apparatus, to BARTROW et al, and U.S. Pat. No.4,144,893, entitled Neuromuscular therapy device, to HICKEY, alsodescribe high voltage capacitive stimulation electrodes. U.S. Pat. No.7,904,180, entitled Capacitive medical electrode, to JUOLA et al,describes a capacitive electrode that includes transcutaneous nervestimulation as one intended application, but that patent does notdescribe stimulation voltages or stimulation waveforms and frequenciesthat are to be used for the transcutaneous stimulation. U.S. Pat. No.7,715,921, entitled Electrodes for applying an electric field in-vivoover an extended period of time, to PALTI, and U.S. Pat. No. 7,805,201,entitled Treating a tumor or the like with an electric field, to PALTI,also describe capacitive stimulation electrodes, but they are intendedfor the treatment of tumors, do not disclose uses involving nerves, andteach stimulation frequencies in the range of 50 kHz to about 500 kHz.

The present invention uses a different method to lower the highstimulation voltage than developing ultra-thin dielectric foils, namely,to use a suitable stimulation waveform, such as the waveform that isdisclosed herein (FIGS. 2B and 2C). That waveform has significantFourier components at higher frequencies than waveforms used fortranscutaneous nerve stimulation as currently practiced. Thus, one ofordinary skill in the art would not have combined the claimed elements,because transcutaneous nerve stimulation is performed with waveformshaving significant Fourier components only at lower frequencies, andnoninvasive capacitive nerve stimulation is performed at highervoltages. In fact, the elements in combination do not merely perform thefunction that each element performs separately. The dielectric materialalone may be placed in contact with the skin in order to performpasteless or dry stimulation, with a more uniform current density thanis associated with ohmic stimulation, albeit with high stimulationvoltages [L. A. GEDDES, M. Hinds, and K. S. Foster. Stimulation withcapacitor electrodes. Medical and Biological Engineering and Computing25(1987): 359-360; Yongmin KIM, H. Gunter Zieber, and Frank A. Yang.Uniformity of current density under stimulating electrodes. CriticalReviews in Biomedical Engineering 17(1990, 6): 585-619]. With regard tothe waveform element, a waveform that has significant Fourier componentsat higher frequencies than waveforms currently used for transcutaneousnerve stimulation may be used to selectively stimulate a deep nerve andavoid stimulating other nerves, as disclosed herein for bothnoncapacitive and capacitive electrodes. But it is the combination ofthe two elements (dielectric interface and waveform) that makes itpossible to stimulate a nerve capacitively without using the highstimulation voltage as is currently practiced.

The use of high dielectric-constant material to cover a metal biomedicalelectrode was apparently first disclosed by PATZOLD et al in 1940 fordiathermy applications [U.S. Pat. No. 2,220,269, entitled Electrodemeans, to PATZOLD et al]. In the 1960s and early 1970s, disclosures ofcapacitive electrodes were motivated by the fact that other(noncapacitive, ohmic) electrodes used invasively as prosthesis implantsexhibit undesirable electrochemical polarization. If the electrode ismade of a noble metal, then the polarization wastes stimulation energy,which is a problem when the electrode is used as a battery-poweredimplant (e.g., cardiac pacemeker). If the electrode is made of anon-noble metal, electrolytic corrosion reactions also occur at thesurface of the electrode, such that the electrode may be destroyed, andpotentially toxic substances may be deposited within the patient's body.Furthermore, for polarizable electrodes, the nature of theelectrode-electrolyte interaction is such that undesirable electronicnonlinearities arise. Use of a nonpolarizable Ag/AgCl electrode tostimulate invasively is not a solution to these problems, because of thetoxicity of silver [Wilson GREATBATCH, Bernard Piersma, Frederick D.Shannon and Stephen W. Calhoun, Jr. Polarization phenomena relating tophysiological electrodes. Annals New York Academy of Science 167(1969,2): 722-44].

In view of the above considerations, several investigators describedcapacitive electrodes that would not generate toxic products where theirimplantation would contact bodily fluids. Such toxic electrolyticproducts are avoided with capacitive electrodes, because the metal ofthe electrode is surrounded by insulating dielectric material. MAUROdescribed a capacitive electrode wherein an insulated wire is surroundedby a saline solution, which is in turn in direct communication withelectrolyte that contacts a nerve or tissue. The electrolytic solution'scommunication was provided by plastic tubing or a single conduit holefor the fluid. In 1971, SCHALDACH described an implanted cardiac pacingelectrode wherein a thin dielectric layer of tantalum oxide covers thesurface of a metallic electrode tip. In 1973 and 1974, GUYTON andHambrecht considered using other dielectric materials to coat animplanted stimulating electrode, including barium titanate and relatedceramic dielectrics, organic dielectric materials such as Teflon,Parylene and Mylar, and Parylene C. [Alexander MAURO. Capacity electrodefor chronic stimulation. Science 132 (1960):356; Max SCHALDACH. Newpacemaker electodes. Transactionsactions of the American Society forArtificial Internal Organs 17(1971): 29-35; David L. GUYTON and F. TerryHambrecht. Capacitor electrode stimulates nerve or muscle withoutoxidation-reduction reaction. Science 181(1973, 4094):74-76; David L.GUYTON and F. Terry Hambrecht. Theory and design of capacitor electrodesfor chronic stimulation. Medical and Biological Engineering 12(1974,5):613-620]. However, use of such implanted capacitive electrodes hasbeen limited, as they may offer little improvement over somenon-capacitive implanted electrodes, in regards to corrosion and thegeneration of toxic products. This is because for noble metalelectrodes, particularly those made of platinum and platinum-iridiumalloys, faradaic reactions are confined to a surface monolayer, suchthat these electrodes are often described as pseudocapacitive, despitethe fact that electron-transfer occurs across the noble metal-electrodeinterface [Stuart F. Cogan. Neural Stimulation and Recording Electrodes.Annu. Rev. Biomed. Eng. 10(2008):275-309].

During the early 1970s, as implanted capacitive electrodes were beingdeveloped for stimulation, non-invasive capacitive electrodes weresimultaneously developed for monitoring or recording purposes, with theobjective of avoiding the use of electrode paste or jelly. Suchpasteless electrodes would be desired for situations involving thelong-term monitoring or recording of physiological signals fromambulatory patients, critical-care patients, pilots, or astronauts.LOPEZ and Richardson (1969) described a capacitive electrode forrecording an ECG. POTTER (1970) described a capacitive electrode with apyre varnish dielectric, for recording an EMG. POTTER and Portnoy (1972)described a capacitive electrode with an integrated impendencetransformer. MATSUO et al (1973) described a capacitive electrode formeasuring an EEG. Patents for capacitive electrodes or systems wereissued to EVERETT et al, to KAUFMAN, and to FLETCHER et al. [AlfredoLOPEZ, Jr. and Philip C. Richardson. Capacitive electrocardiographic andbioelectric electrodes. IEEE Trans Biomed Eng. 16(1969, 1):99; AllanPOTTER. Capacitive type of biomedical electrode. IEEE Trans Biomed Eng.17 (1970, 4):350-351; U.S. Pat. No. 3,568,662, entitled Method andapparatus for sensing bioelectric potentials, to EVERETT et al; R. M.DAVID and W. M. Portnoy. Insulated electrocardiogram electrodes. MedBiol Eng. 10(1972, 6):742-51; U.S. Pat. No. 3,744,482, entitled Drycontact electrode with amplifier for physiological signals, to KAUFMANet al; MATSUO T, Iinuma K, Esashi M. A barium-titanate-ceramicscapacitive-type EEG electrode. IEEE Trans Biomed Eng 20 (1973,4):299-300; U.S. Pat. No. 3,882,846, entitled Insulatedelectrocardiographic electrodes, to FLETCHER et al].

It is understood that although non-invasive capacitive electrodes can beused as dry, pasteless electrodes, they may also be used to contact skinthat has been wetted (e.g., with tap water or a more conventionalelectrolytic material) to make the electrode-skin contact (here thedielectric constant) more uniform. In fact, perspiration from the skinwill provide some moisture to the boundary between electrode and skininterface. Furthermore, not all non-invasive, pasteless electrodes arecapacitive electrodes [BERGEY, George E., Squires, Russell D., andSipple, William C. Electrocardiogram recording with pastelesselectrodes. IEEE Trans Biomed Eng. 18(1971, 3):206-211; GEDDES L A,Valentinuzzi M E. Temporal changes in electrode impedance whilerecording the electrocardiogram with “dry” electrodes. Ann Biomed Eng.1(1973, 3): 356-67; DELUCA C J, Le Fever R S, Stulen F B. Pastelesselectrode for clinical use. Med Biol Eng Comput. 17(1979, 3):387-90;GONDRAN C, Siebert E, Fabry P, Novakov E, Gumery P Y. Non-polarisabledry electrode based on NASICON ceramic. Med Biol Eng Comput. 33(1995, 3Spec No):452-457; Yu Mike CHI, Tzyy-Ping Jung, and Gert Cauwenberghs.Dry-Contact and noncontact biopotential electrodes: methodologicalreview. IEEE Reviews in Biomedical Engineering 3(2010):106-119; BenjaminBLANKERTZ, Michael Tangermann, Carmen Vidaurre, Siamac Fazli, ClaudiaSannelli, Stefan Haufe, Cecilia Maeder, Lenny Ramsey, Irene Sturm,Gabriel Curio and Klaus-Robert Muller. The Berlin brain-computerinterface: non-medical uses of BCI technology. Front Neurosci.4(2010):198. doi: 10.3389/fnins.2010.00198, pp 1-17]. Moreover, it isnoted that some dry electrodes that purport to be non-invasive areactually minimally invasive, because they have microtips that impale theskin [N. S. DIAS, J. P. Carmo, A. Ferreir da Silva, P. M. Mendes, J. H.Correia. New dry electrodes based on iridium oxide (IrO) fornon-invasive biopotential recordings and stimulation. Sensors andActuators A 164 (2010): 28-34; U.S. Pat. No. 4,458,696, entitledT.E.N.S. Electrode, to LARIMORE; U.S. Pat. No. 5,003,978, entitledNonpolarizable dry biomedical electrode, to DUNSEATH Jr.].

Disadvantages of the above-mentioned non-invasive capacitive electrodesinclude susceptibility to motion artifact, a high inherent noise level,and susceptibility to change with the presence of perspiration, which inpractice have tended to outweigh their advantages of being pasteless ordry, and exhibition of uniform current density. However, in recentyears, such electrodes have been improved with the objective of beingused even without contacting the skin, wherein they may record anindividual's ECG or EEG when the electrode is placed within clothing,head and chest bands, chairs, beds, and the like [Yu Mike CHI, Tzyy-PingJung, and Gert Cauwenberghs. Dry-Contact and noncontact biopotentialelectrodes: methodological review. IEEE Reviews in BiomedicalEngineering 3(2010):106-119; Jaime M. LEE, Frederick Pearce, Andrew D.Hibbs, Robert Matthews, and Craig Morrissette. Evaluation of aCapacitively-Coupled, Non-Contact (through Clothing) Electrode or ECGMonitoring and Life Signs Detection for the Objective Force Warfighter.Paper presented at the RTO HFM Symposium on “Combat Casualty Care inGround Based Tactical Situations: Trauma Technology and EmergencyMedical Procedures”, held in St. Pete Beach, USA, 16-18 Aug. 2004, andpublished in RTO-MP-HFM-109: pp 25-1 to 25-10; HEUER S., Martinez, D.R., Fuhrhop, S., Ottenbacher, J. Motion artefact correction forcapacitive ECG measurement. Biomedical Circuits and Systems Conference(BioCAS) Proceeding 26-28 Nov. 2009, pp 113-116; Enrique SPINELLI andMarcelo Haberman. Insulating electrodes: a review on biopotential frontends for dielectric skin-electrode interfaces. Physiol. Meas. 31 (2010)S183-S198; A SEARLE and L Kirkup. A direct comparison of wet, dry andinsulating bioelectric recording electrodes. Physiol. Meas. 21 (2000):271-283; U.S. Pat. No. 7,173,437, entitled Garment incorporatingembedded physiological sensors, to HERVIEUX et al; U.S. Pat. No.7,245,956 entitled Unobtrusive measurement system for bioelectricsignals, to MATTHEWS et al]. Those disclosures address the problems ofmotion artifact and noise. For contact capacitive electrodes, the issueof perspiration may be addressed by placing indented channels in theskin-side surface of the dielectric material, parallel to the electrodesurface, placing absorbent material around the periphery of theelectrode, then wicking the sweat through the channels into theabsorbent material.

Capacitive electrodes have also been used to stimulate tissue other thannerves. They are used as the dispersive electrode in electrosurgery[U.S. Pat. No. 4,304,235, entitled Electrosurgical electrode, toKAUFMAN; U.S. Pat. No. 4,387,714, entitled Electrosurgical dispersiveelectrode, to GEDDES et al; U.S. Pat. No. 4,669,468, entitledCapacitively coupled indifferent electrode to CARTMELLet al; YongminKIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of current densityunder stimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6) 585-619]. Capacitive electrodes have also been usedinvasively to treat tumors, by implanting a pair of insulated wires inthe vicinity of the tumor [Eilon D. Kirson, Zoya Gurvich, RosaSchneiderman, Erez Dekel, Aviran Itzhaki, Yoram Wasserman, RachelSchatzberger, and Yoram Palti. Disruption of cancer cell replication byalternating electric fields. Cancer Research 64(2004): 3288-3295].Similarly, they have also been used to treat tumors non-invasively [U.S.Pat. No. 7,715,921, entitled Electrodes for applying an electric fieldin-vivo over an extended period of time, to PALTI; U.S. Pat. No.7,805,201, entitled Treating a tumor or the like with an electric field,to PALTI]. However, none of these applications that involve stimulatingtissue other than nerves, and none of the other non-invasive recordingapplications, and none of the invasive applications disclose methods ordevices that would demonstrate how to use capacitive electrodes tostimulate nerves noninvasively using a low-voltage stimulator.

Another embodiment of the disclosed stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 1) is the conducting material itself. FIGS. 5A and 5Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 1), and the power-levelcontroller is attached to the control unit (330 in FIG. 1) of thedevice. The power source battery and power-level controller, as well asthe impulse generator (310 in FIG. 1) are located (but not shown) in therear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 inFIG. 1) to the stimulator's electrodes 56. The two electrodes 56 areshown here to be elliptical metal discs situated between the headcompartment 57 and rear compartment 55 of the stimulator 50. A partition58 separates each of the two head compartments 57 from one another andfrom the single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 1) to each headcompartment 57. Each partition 58 may also slide towards the head of thedevice in order to dispense conducting gel through the mesh apertures51. The position of each partition 58 therefore determines the distance59 between its electrode 56 and mesh openings 51, which is variable inorder to obtain the optimally uniform current density through the meshopenings 51. The outside housing of the stimulator 50, as well as eachhead compartment 57 housing and its partition 58, are made ofelectrically insulating material, such as acrylonitrile butadienestyrene, so that the two head compartments are electrically insulatedfrom one another.

Although the embodiment in FIG. 5 is shown to be a non-capacitivestimulator, it is understood that it may be converted into a capacitivestimulator by replacing the mesh openings 51 with a dielectric material,such as a sheet of Mylar, or by covering the mesh openings 51 with asheet of such dielectric material.

In the preferred embodiments, electrodes are made of a metal, such asstainless steel. However, in other embodiments, the electrodes may havemany other sizes and shapes, and they may be made of other materials[Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E. Leane, M.Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigation of theeffect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35.

For example, there may be more than two electrodes; the electrodes maycomprise multiple concentric rings; and the electrodes may bedisc-shaped or have a non-planar geometry. They may be made of othermetals or resistive materials such as silicon-rubber impregnated withcarbon that have different conductive properties [Stuart F. COGAN.Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng.2008. 10:275-309; Michael F. NOLAN. Conductive differences in electrodesused with transcutaneous electrical nerve stimulation devices. PhysicalTherapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 3 to 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 3to 5 provide a uniform surface current density, which would otherwise bea potential advantage of electrode arrays, and which is a trait that isnot shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jørgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71(1999): 4944-4950]. Infact, patients found the design shown in FIGS. 3 to 5 to be less painfulin a direct comparison with a commercially available grid-patternelectrode [UltraStim grid-pattern electrode, Axelggard ManufacturingCompany, 520 Industrial Way, Fall brook Calif., 2011]. The embodiment ofthe electrode that uses capacitive coupling is particularly suited tothe generation of uniform stimulation currents [Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6): 585-619].

The stimulator designs shown in FIGS. 3 to 5 situate the electroderemotely from the surface of the skin within a chamber, with conductingmaterial placed in the chamber between the skin and electrode. Such achamber design had been used prior to the availability of flexible,flat, disposable electrodes [U.S. Pat. No. 3,659,614, entitledAdjustable headband carrying electrodes for electrically stimulating thefacial and mandibular nerves, to Jankelson; U.S. Pat. No. 3,590,810,entitled Biomedical body electode, to Kopecky; U.S. Pat. No. 3,279,468,entitled Electrotherapeutic facial mask apparatus, to Le Vine; U.S. Pat.No. 6,757,556, entitled Electrode sensor, to Gopinathan et al; U.S. Pat.No. 4,383,529, entitled Iontophoretic electrode device, method and gelinsert, to Webster; U.S. Pat. No. 4,220,159, entitled Electrode, toFrancis et al. U.S. Pat. No. 3,862,633, U.S. Pat. No. 4,182,346, andU.S. Pat. No. 3,973,557, entitled Electrode, to Allison et al; U.S. Pat.No. 4,215,696, entitled Biomedical electrode with pressurized skincontact, to Bremer et al; and U.S. Pat. No. 4,166,457, entitled Fluidself-sealing bioelectrode, to Jacobsen et al.] The stimulator designsshown in FIGS. 3 to 5 are also self-contained units, housing theelectrodes, signal electronics, and power supply. Portable stimulatorsare also known in the art, for example, U.S. Pat. No. 7,171,266,entitled Electro-acupuncture device with stimulation electrode assembly,to Gruzdowich]. One of the novelties or the present invention is thattwo or more remote electrodes are configured for placement relative tothe axis of a deep, long nerve, such that the stimulator along with acorrespondingly suitable stimulation waveform shapes the electric field,producing a selective physiological response by stimulating that nerve,but avoiding substantial stimulation of nerves and tissue other than thetarget nerve, particularly avoiding the stimulation of nerves thatproduce pain.

Examples in the remaining disclosure will be directed to methods forusing the disclosed electrical stimulation devices for treating apatient. These applications involve stimulating the patient in andaround the patient's neck. However, it will be appreciated that thesystems and methods of the present invention might be applied equallywell to other nerves of the body, including but not limited toparasympathetic nerves, sympathetic nerves, and spinal or cranialnerves. As examples, the disclosed devices may used to treat particularmedical conditions, by substituting the devices disclosed herein for thestimulators disclosed in the following patent applications.

Applicant's commonly assigned co-pending patent application, Ser. No.12/964,050, entitled Toroidal Magnetic Stimulation Devices and Methodsof Therapy, disclosed methods for using the device to treat suchconditions as post-operative ileus, dysfunction associated withTNF-alpha in Alzheimer's disease, postoperative cognitive dysfunction,rheumatoid arthritis, bronchoconstriction, urinary incontinence and/oroveractive bladder, and sphincter of Oddi dysfunction.

Another commonly assigned co-pending application, Ser. No. 13/005,005,entitled Non-invasive Treatment of Neurodegenerative Diseases, disclosedmethods and devices for treating neurodegenerative diseases moregenerally, including Alzheimer's disease and its precursor mildcognitive impairment (MCI), Parkinson's disease (including Parkinson'sdisease dementia) and multiple sclerosis, as well as postoperativecognitive dysfunction and postoperative delirium. The devices andmethods may also be used to treat conditions that were not disclosed inthose patent applications, such as allergic rhinitis, headaches,particularly tension headaches, cluster headaches, sinus headaches andmigraine headaches [Alberto Proietti CECCHINI, Eliana Mea, VincenzoTullo, Marcella Curone, Angelo Franzini, Giovanni Broggi, Mario Savino,Gennaro Bussone, Massimo Leone. Vagus nerve stimulation indrug-resistant daily chronic migraine with depression: preliminary data.Neurol Sci (2009) 30 (Suppl 1):5101-5104].

Another commonly assigned co-pending application, Ser. No. 13/024,727,entitled Non-invasive methods and devices for inducing euphoria in apatient and their therapeutic application, disclosed methods and devicesfor treating depression, premenstrual symptoms, behavioral disorders,insomnia, and usage to perform anesthesia.

Another commonly assigned co-pending application, Ser. No. 13/109,250,entitled Electrical and magnetic stimulators used to treatmigraine/sinus headache and comorbid disorders, disclosed methods anddevices used to treat headaches including migraine and clusterheadaches, as well as anxiety disorders.

Another commonly assigned co-pending application, Ser. No. 13/109,250,entitled Electrical and magnetic stimulators used to treatmigraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, andcomorbid disorders, disclosed methods for treating rhinitis, sinusitisand rhinosinusitis.

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3 to 5 to stimulatethe vagus nerve at that location in the neck, in which the stimulatordevice 50 in FIG. 5 is shown to be applied to the target location on thepatient's neck as described above. For reference, locations of thefollowing vertebrae are also shown: first cervical vertebra 71, thefifth cervical vertebra 75, the sixth cervical vertebra 76, and theseventh cervical vertebra 77.

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin. The vagusnerve 60 is identified in FIG. 7, along with the carotid sheath 61 thatis identified there in bold peripheral outline. The carotid sheathencloses not only the vagus nerve, but also the internal jugular vein 62and the common carotid artery 63. Features that may be identified nearthe surface of the neck include the external jugular vein 64 and thesternocleidomastoid muscle 65. Additional organs in the vicinity of thevagus nerve include the trachea 66, thyroid gland 67, esophagus 68,scalenus anterior muscle 69, and scalenus medius muscle 70. The sixthcervical vertebra 76 is also shown in FIG. 7, with bony structureindicated by hatching marks.

If it is desired to maintain a constant intensity of stimulation in thevicinity of the vagus nerve (or any other nerve or tissue that is beingstimulated), methods may also be employed to modulate the power of thestimulator in order to compensate for patient motion or other mechanismsthat would otherwise give rise to variability in the intensity ofstimulation. In the case of stimulation of the vagus nerve, suchvariability may be attributable to the patient's breathing, which mayinvolve contraction and associated change in geometry of thesternocleidomastoid muscle that is situated close to the vagus nerve(identified as 65 in FIG. 7). Methods for compensating for motion andother confounding factors were disclosed by the present applicant incommonly assigned co-pending application U.S. Ser. No. 12/859,568,entitled Non-Invasive Treatment of Bronchial Constriction, to SIMON,which is hereby incorporated by reference.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. The position and angular orientation of thedevice are adjusted about that location until the patient perceivesstimulation when current is passed through the stimulator electrodes.The applied current is increased gradually, first to a level wherein thepatient feels sensation from the stimulation. The power is thenincreased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 6 or 7).The stimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient. Stimulationparameters for each patient are adjusted on an individualized basis.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a time-varying sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect. For example, thehypothalamus is well known to be responsive to the presence of brightlight, so exposing the patient to bright light that is fluctuating withthe same stimulation frequency as the vagus nerve (or a multiple of thatfrequency) may be performed in an attempt to enhance the role of thehypothalamus in producing the desired therapeutic effect. Such pairedstimulation does not rely upon neuronal plasticity and is in that sensedifferent from other reports of paired stimulation [Navzer D. ENGINEER,Jonathan R. Riley, Jonathan D. Seale, Will A. Vrana, Jai A. Shetake,Sindhu P. Sudanagunta, Michael S. Borland and Michael P. Kilgard.Reversing pathological neural activity using targeted plasticity. Nature(2011): published online doi:10.1038/nature09656].

Kits

The devices described herein can be packaged in kit form. In oneembodiment, the kit includes a handheld battery powered portablestimulator device useful for stimulating a nerve in a subject andinstructions for its use. Kits of the invention may include any of thefollowing, separately or in combination: nerve stimulator, conductinggel or fluid and instructions.

Each stimulator kit is supplied with a stimulator in a fully operationalstate and is suitable for storage or immediate use. A kit may optionallyprovide additional components that are useful in practicing the methods,training and procedures of the embodiment, such as conductive solutionsor gels.

An example of a kit includes a stimulator device and instructions forhow to use the device. The instructions are generally recorded on asuitable recording medium. For example, the instructions may be printedon a substrate, such as paper or plastic. As such, the instructions maybe present in the kits as a package insert, in the labeling of thecontainer of the kit or components thereof (i.e., associated with thepackaging or sub-packaging). In other embodiments, the instructions arepresent as an electronic storage data file present on a suitablecomputer readable storage medium, e.g., CD-ROM, diskette, etc. Theinstructions may take any form, including complete instructions on howto use the device, or references, directing a user to using additionalsources for instructions, such as, for example, a website address withinstructions posted on the world wide web).

The following exemplary instructions are offered by way of illustrationand not by way of limitation.

Instructions

A stimulator device adapted for use on the vagus nerve may benon-invasively placed onto the right side of a subject's neck by medicalpersonnel, by the subject, or by a third-party administrator. In someembodiments, the device works as follows. Medical personnel, thesubject, or the administrating third-party removes protective caps fromtwo simulation surfaces located on the stimulator. If the stimulator isbeing used for the first time, protective plastic coverings or films mayalso have to be removed from the stimulation surfaces.

The subject should be placed in a seated position with his/her headtilted up and to the left, thereby exposing the right side of thesubject's neck. All jewelry in the head and neck region of the subjectshould be removed. The stimulator device should be aligned with thefollowing anatomical structures of the subject: in front of thesternocleidomastoid muscle; just below the jaw line, and parallel to thetrachea. Prior to actual placement of the simulator on the subject, asmall amount, (approximately 1 cc), of suitable electrode gel should beplaced on each of the stimulation surfaces.

Next, the stimulator device is ready to be turned on. Medical personnel,the subject, or the administrator should slowly turn the thumbwheeltowards the stimulator surfaces until an audible click is heard. Whenthe stimulator is ready to use, i.e., operational, a LED illuminatorwill turn green and the device will emit an audible tone or beep. Themedical personnel, subject or administrator should position thestimulator on the right side of the subject's neck in the regiondescribed above. With the stimulator in place, the user slowly increasesthe stimulation intensity by gradually rotating the thumbwheel towardsthe subject's neck until the maximum tolerated level of comfort isreached by the subject. The subject may experience a slight tremor ofthe muscles under the stimulation surfaces. If the muscle contractionsare too strong or uncomfortable, the level of stimulation can be reducedby adjusting the thumbwheel.

Because of the anatomical differences between patients and thepositioning of the stimulator, it may be appropriate to adjust thestimulation intensity to the highest setting that is comfortablytolerated by the subject. Treatment may, however, be effective even atlevels at or before a subject senses a slight tremor of the musclesunder the skin. Once the correct intensity is set, the stimulator shouldbe held in place for the entire treatment period, (90 seconds in anembodiment). Note, the stimulator may be active for up to 120 secondafter it has been turned on to give the subject, medical personnel, orthe third-party administrator ample time to position the device and setthe proper stimulation intensity.

If unpleasant skin or muscle sensations persists, such that the subjectcannot tolerate treatment for 90 seconds, then the following procedureshould be followed: (a) remove the stimulator from the subject's neck,(b) lower the stimulation intensity by rotating the thumbwheel away fromthe stimulation surfaces; (c) reposition the stimulator on the subjectsneck; and (d) if stimulation is still intolerable, turn the stimulatoroff and discontinue treatment.

After treatment is completed, the stimulator should be turned off byrotating the thumbwheel until it clicks. Any excess gel should becleaned from the stimulation surfaces with a soft dry cloth. Theprotective caps should be replaced, and the stimulator stored in a cleandry location for the next use.

In various embodiments the entire treatment period may be a fixed timeperiod, such as, for example, 30 seconds, 40 seconds, 50 seconds, 60seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds, 110 seconds,120 seconds, or greater than 120 seconds, or the entire treatment periodmay be a variable time period depending on a variety of factors, suchas, for example, the weight of the patient, the medical condition of thepatient, including based on pulse, blood pressure, blood oxygen levels,etc., type of condition being treated, or any other factor. Thestimulator may be active for the entire treatment period or a period oftime greater than the entire treatment period.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. An apparatus for modulating one or more nerveswithin a body of a patient comprising: an enclosure; a source of energyfor generating an electric field housed within the enclosure; one ormore electrodes coupled to the source of energy and housed within theenclosure; an electrically conductive interface coupled to theelectrodes and positionable against an outer skin surface of thepatient; a volume of electrically conductive fluid residing within theenclosure and at least partially surrounding a portion of theelectrodes, the volume of electrically conductive fluid electricallycoupling the electrodes with the interface; and wherein the source ofenergy is configured to deliver one or more electrical impulses from theelectrodes through the volume of electrically conductive fluid, theinterface and the outer skin surface to a nerve at a target regionwithin the patient.
 2. The apparatus of claim 1 wherein the targetregion is a nerve located at least 1-2 cm beyond the outer skin surface.3. The apparatus of claim 1 where the target region is a nerve islocated at least 2-5 cm beyond the outer skin surface.
 4. The apparatusof claim 1 wherein the volume of electrically conductive fluid comprisesa solution of electrolytes.
 5. The apparatus of claim 1 wherein thevolume of electrically conductive fluid comprises a conductive gel. 6.The apparatus of claim 1 further comprising a housing having an outerenclosure enclosing the electrodes and the conduction medium, wherein atleast a portion of the outer enclosure comprises one or more openingsfor containing the electrically conductive interface.
 7. The apparatusof claim 6 wherein the electrically conductive interface and the outerenclosure substantially contain the conduction medium therein.
 8. Theapparatus of claim 1 wherein the electrically conductive interfacecomprises stainless steel.
 9. The apparatus of claim 1 wherein thesource of energy is configured to generate an electrical fieldcomprising bursts of pulses with a frequency of about 5 to about 100bursts per second.
 10. The apparatus of 1 wherein the source of energyis configured to generate an electrical field comprising bursts ofbetween 1 and 20 pulses with each pulse about 50-1000 microseconds induration.
 11. The apparatus of claim 1 wherein the electricallyconductive interface comprises two discs and the apparatus furthercomprising two corresponding electrodes, and wherein the electrodes arespaced from each disc by about 0.25 to 4 times the diameter of thecorresponding disc.